Mechanisms by which T cell populations are generated are relevant to considerations of immunoreconstitution in situations in which T cell depletion occurs. Studies in rhesus monkeys investigating T cell generation following T cell depleted autologous marrow transplantation provided evidence that residual T cells in infused T cell-depleted marrow play a central role in the generation of subsequent T cell populations. This possibility was confirmed in murine studies in which three T cell progenitor pools were identified which contribute to final T cell repopulation following marrow transplantation. It was found that CD4+ T cells arising from a peripheral, mature lymphocyte precursor pool were of memory phenotype, and that only CD4+ T cells generated by a thymic pathway contained large numbers of naive T cells. This information has been applied to studies of T cell generation in patients receiving chemotherapy which have shown an age dependence on generation of CD4+ T cells by the thymus and have validated this approach to study T cell generation in humans. In contrast to studies in children, collaborative investigations have shown that CD4+ T cell regeneration proceeds primarily by way of mature T cell expansion in adults. Parallel studies in this project have shown that such expansion is antigen driven, is prone to skewing, and is cytokine modulated. Two cytokines were identified as active in modifying CD4+ T cell reconstitution, namely IL-2 and IL-7. The former acted through upregulation of thymic dependent generation of T cells; the latter was the only cytokine identified which upregulated T cell regeneration by peripheral expansion of mature T cells in the absence of a functional thymus. These studies have also characterized CD8+ T cell generation in mice and humans. Unlike the case for CD4+ T cells, subsets of CD8+ T cells have been identified which appear to be generated directly from marrow precursors through extrathymic pathways. In other investigations, TGF-beta has been identified as a critical negative regulator of CD8+ T cell homeostesis. In the absence of TGF-beta signaling, CD8+ T cells expand with consequent inversion of the CD4,8 ratio, V-beta skewing, and neoplastic transformation. These issues are being studied in transgenic models to further delineate the role of cytokines in T cell homeostasis and thymic involution. Formerly Z01 CB 09288-09 EIB.